Over the past 20 years, research on animal models as well as human subjects has demonstrated that the vestibular system contributes to regulating the distribution of blood in the body through effects on the sympathetic nervous system. Elimination of vestibular inputs attenuates the increase in vascular resistance that ordinarily occurs in the lower body during head-up tilts, resulting in increased blood flow to the hindlimbs. Presumably, this increased perfusion of the hindlimbs during head-up rotations produces peripheral blood pooling and a decrease in venous return to the heart, although this hypothesis has not been verified experimentally. Specific Aim 1 will determine whether removal of labyrinthine signals provides for a reduction in venous blood flow from the lower body during head-up body alterations, which would increase susceptibility for orthostatic hypotension. Head-up rotations additionally result in an increase in vascular resistance in the forelimb, although a bilateral vestibular neurectomy does not attenuate this response, as occurred in the hindlimb. This result indicates the existence of neural pathways that independently control sympathetic outflow to the forelimb and hindlimb. Specific Aim 2 will employ neuroanatomical methods to ascertain whether separate populations of neurons in the principal vasomotor region of the brainstem, the rostral ventrolateral medulla (RVLM), regulate sympathetic outflow to the upper and lower body. Additionally, Specific Aim 2 will utilize neurophysiological recordings to determine whether RVLM neurons regulating sympathetic outflow to the upper and lower body respond differently to vestibular stimulation. Although removal of vestibular inputs through a bilateral vestibular neurectomy attenuates cardiovascular adjustments during head-up postural alterations, the ability to rapidly adjust blood pressure and blood flow during such movements returns over time. Recent findings suggest that baroreceptor and vestibular inputs adjust sympathetic outflow during movement in an additive fashion. In addition, RVLM neurons receive convergent vestibular and baroreceptor inputs and provide the major pathway relaying both signals to sympathetic preganglionic neurons. Thus, increases in the response gain of RVLM neurons to baroreceptor inputs following the elimination of labyrinthine signals could offset the loss of vestibulo-sympathetic responses. Specific Aim 3 will establish whether responses of RVLM neurons to head-up tilts are attenuated following a bilateral labyrinthectomy, but recover in parallel with enhanced responses of the cells to baroreceptor inputs. These experiments will contribute to understanding the mechanisms through which cardiovascular adjustments are made during movement and changes in posture, and may provide insights towards developing therapeutic approaches to alleviate autonomic disturbances in patients with central or peripheral vestibular lesions. PUBLIC HEALTH RELEVANCE Standing from a lying or sitting position produces considerable challenges to the cardiovascular system, as gravity causes blood to shift from the thorax to the extremities, resulting in a decrease in the return of blood to the heart. This condition, called orthostatic intolerance, can bring about fainting if not corrected quickly. The proposed research considers the role of the vestibular system in compensating for orthostatic hypotension. [unreadable] [unreadable] [unreadable]